§Warfarin clearance is by hepatic metabolism largely mediated by CYP2C9(part of the cytochrome P450 system)

§Most important polymorphisms are CYP2C9*2 and *3 which result in a 30 and 80% reduction in enzymatic activity respectively, resulting in increased anticoagulant effect.

§VKORC1 is the enzyme inhibited by warfarin

§Polymorphisms result in either low or high level haplotypes; high level haplotypes require higher doses.

§Factor IX propeptide mutations

§Highly sensitive to warfarin; APTT >> PT

§Can treat with warfarin, but monitor FIX (10-15%)

Alternatives

§Controversial, but could consider long term secondary prophylaxis with a reduced INR after an initial period of normal anticoagulation – may be appropriate for those in whom frequent INR monitoring is difficult.